Insulin-dependent diabetes mellitus (IDDM) in BB rats is characterized by T cell-mediated destruction of pancreatic beta cells, insulin deficiency, and hyperglycemia. Diabetes prone (DP) BB rats develop hyperglycemia spontaneously. Diabetes resistant (DR) BB rats develop diabetes only when challenged with environmental perturbants and provide the only available animal model of virus-induced autoimmune diabetes amenable to study at the genetic level. The only element known to be common to the genetic control of spontaneous or virus-associated IDDM in rat, mouse, and human is the requirement for a permissive major histocompatibility complex (MHC). In the previous grant period, we mapped a major non-MHC locus, designated iddm4, likely to be responsible for autoreactivity in BB rats. Building on that foundation, the goals of this proposal are 1) fine mapping and identification of iddm4 and 2) mapping of loci that determine whether IDDM will occur in animals that are exposed to a diabetogenic virus. We hypothesize that iddm4 is a major IDDM susceptibility locus and will be a critical genetic factor in viral diabetogenesis. Specific Aim No. 1 is to create rat populations for fine mapping iddm4, for identifying additional diabetes-modifying (iddm-m) loci, and for determining their epistatic interactions. This will be done using an iddm4 congenic series and an F2 intercross between (DR x WF)F1 rats. Specific Aim No. 2 is to identify the activities and mechanism of action of iddm4. We determine if adoptive transfer of IDDM by thymocytes and bone marrow is controlled by iddm4. Specific Aim No. 3 is to map the genetic loci that modify the expression of IDDM in response to infection with Kilham rat virus (KRV). We will test iddm4 congenic, backcross, and F2 cohorts for IDDM after infection with KRV. Specific Aim No. 4 is to identify and characterize iddm4. We will use positional cloning, candidate gene, and representational difference analyses as required to identify iddm4. Our belief and ultimate hope is that understanding the genetics of IDDM in BB rats will lead to the identification of analogous loci and genes relevant to the pathogenesis and prevention of human IDDM.